Submissions for variant NM_007294.4(BRCA1):c.4327C>T (p.Arg1443Ter)

dbSNP: rs41293455

Total submissions: 50

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000019244	SCV000282327	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048523	SCV000076536	pathogenic	Hereditary breast ovarian cancer syndrome	2024-12-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1443*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 16030099, 19656415, 22798144, 23233716). It is commonly reported in individuals of French Canadian ancestry (PMID: 10422801, 11250694, 15883839, 20694749). This variant is also known as 4446C>T. ClinVar contains an entry for this variant (Variation ID: 17675). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131880	SCV000186935	pathogenic	Hereditary cancer-predisposing syndrome	2024-12-03	criteria provided, single submitter	clinical testing	The p.R1443* pathogenic mutation (also known as c.4327C>T), located in coding exon 11 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4327. This changes the amino acid from an arginine to a stop codon within coding exon 11. This mutation is a well-known French Canadian founder mutation and has been reported in numerous breast and/or ovarian cancer families to date (Ferla R et al. Ann. Oncol. 2007 Jun;18 Suppl 6:vi93-8; Ghadirian P et al. Clin. Genet. 2009 Nov;76(5):421-6; Janavicius R et al. EPMA J. 2010 Sep;1(3):397-412; Zhang S et al. Gynecol. Oncol. 2011 May;121(2):353-7). In addition to French Canadians, this mutation has also been identified in multiple other populations (McKean-Cowdin R et al. Hum. Genet. 2005 May;116(6):497-506; Donenberg T et al. Breast Cancer Res. Treat. 2016 Aug;159(1):131-8; Jalkh N et al. BMC Med Genomics 2017 Feb;10(1):8; Palmero EI et al. Sci Rep. 2018 Jun;8(1):9188; Singh J et al. Breast Cancer Res. Treat. 2018 Jul;170(1):189-196). Of note, this alteration is also designated as 4446C>T and R1443X in some published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000235131	SCV000210173	pathogenic	not provided	2019-11-04	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4446C>T; This variant is associated with the following publications: (PMID: 23233716, 26028024, 25371446, 27463008, 28127413, 19656415, 9625424, 7493024, 8533757, 28111427, 29446198, 16905680, 25525159, 18680205, 23341105, 22401979, 15382066, 20694749, 15883839, 10090482, 23199084, 17148771, 11307153, 10486320, 7894491, 21324516, 27469594, 27184744, 27393621, 26541979, 28049106, 27783335, 16030099, 25236687, 27533253, 26976419, 21120943, 27221827, 26911350, 25504618, 17688236, 27286788, 25085752, 27553291, 28283652, 28392550, 19863560, 15726418, 25652403, 17591843, 19241424, 11179017, 17221156, 22798144, 9792861, 10682662, 26295337, 19329713, 16417652, 10422801, 15951958, 18821011, 10984458, 8990217, 21203900, 8571953, 28985766, 26681312, 28993434, 29907814, 29470806, 28724667, 30702160, 30630528, 30078507, 30720243, 30322717, 30093976, 31090900, 32467295, 33646313, 11597388, 31447099, 31825140, 32341426, 32885271, 30875412, 31742824, 33087929)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735445	SCV000219242	pathogenic	Breast and/or ovarian cancer	2023-06-23	criteria provided, single submitter	clinical testing
Counsyl	RCV000019244	SCV000220762	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-10-02	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000235131	SCV000225648	pathogenic	not provided	2018-05-25	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories, University of Michigan	RCV000019244	SCV000267710	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235131	SCV000296337	pathogenic	not provided	2023-07-06	criteria provided, single submitter	clinical testing	The BRCA1 c.4327C>T (p.Arg1443*) variant causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in individuals with breast cancer (PMID: 33646313 (2021), 32885271 (2021), 32854451 (2020), 32341426 (2020), 32029870 (2020), 28724667 (2017)) and endometrial cancer (PMID: 28049106 (2017)). This variant has also been described as a French founder mutation (PMID: 23199084 (2010). The frequency of this variant in the general population, 0.000085 (3/35428 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
GeneKor MSA	RCV000239083	SCV000296802	pathogenic	not specified	2016-07-01	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000019244	SCV000325921	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131880	SCV000537634	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-09	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 12 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 30 individuals affected with breast, ovarian and uterine cancer (PMID: 7894491, 10422801, 10682662, 11179017, 15726418, 17221156, 19656415, 19863560, 20104584, 21324516, 22798144, 26681312, 27553291, 28724667, 28993434, 29470806, 33471991; Leiden Open Variation Database DB-ID BRCA1_000312). A breast cancer case-control meta-analysis detected this variant in 9/41890 cases and 1/41607 unaffected individuals with an OR 8.3 (95% CI 1.05-16.0) (PMID: 28283652). This variant has been detected in over 100 suspected hereditary breast and ovarian cancer families (PMID: 7493024, 16030099, 18821011, 19241424, 19329713, 21203900, 23233716, 29907814), in which haplotype analyses suggest that this was a founder mutation in the French-Canadian population and also arose independently worldwide (PMID: 9792861, 15883839, 23199084). This variant has been identified in 7/282760 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Baylor Genetics	RCV000159989	SCV000540934	pathogenic	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Genologica Medica	RCV000019244	SCV000577931	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-01-01	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000048523	SCV000588057	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000019244	SCV000593678	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-11-29	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000239083	SCV000602710	pathogenic	not specified	2019-02-21	criteria provided, single submitter	clinical testing	The BRCA1 c.4327C>T; p.Arg1443Ter variant (rs41293455), also known as 4446C>T for traditional nomenclature, is reported in the literature in multiple individuals with hereditary breast and ovarian cancer syndrome (Castilla 1994, de Jonge 2017, Rashid 2016, Sun 2017, Susswein 2016, Zhang 2011). This variant is also described as a founder variant in the French Canadian population (Cavallone 2010, Neuhausen 2000, Tonin 1999, Vezina 2005). It is reported by multiple laboratories in ClinVar (Variation ID: 17675), and found in the general population with a low overall allele frequency of 0.002% (6/246148 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Castilla LH et al. Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer. Nat Genet. 1994 Dec;8(4):387-91. Cavallone L et al. Comprehensive BRCA1 and BRCA2 mutation analyses and review of French Canadian families with at least three cases of breast cancer. Fam Cancer. 2010 Dec;9(4):507-17. de Jonge MM et al. Linking uterine serous carcinoma to BRCA1/2-associated cancer syndrome: A meta-analysis and case report. Eur J Cancer. 2017 Feb;72:215-225. Neuhausen SL. Founder populations and their uses for breast cancer genetics. Breast Cancer Res. 2000;2(2):77-81. Rashid MU et al. High prevalence and predominance of BRCA1 germline mutations in Pakistani triple-negative breast cancer patients. BMC Cancer. 2016 Aug 23;16(1):673. Sun J et al. Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients. Clin Cancer Res. 2017 Oct 15;23(20):6113-6119. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32. Tonin PN et al. Founder BRCA1 and BRCA2 mutations in French Canadian ovarian cancer cases unselected for family history. Clin Genet. 1999 May;55(5):318-24. Vezina H et al. Molecular and genealogical characterization of the R1443X BRCA1 mutation in high-risk French-Canadian breast/ovarian cancer families. Hum Genet. 2005 Jul;117(2-3):119-32. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011 May 1;121(2):353-7.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000048523	SCV000605740	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-09	criteria provided, single submitter	clinical testing	The p.Arg1443X variant in BRCA1 has been previously reported in >100 individuals with BRCA1-associated cancers and is considered to be a French-Canadian founder mutation (Vézina 2005 PMID:15883839, Hall 2009 PMID:19241424). It has also been identified in 0.002% (1/41432) African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This nonsense variant leads to a premature termination codon at position 1443, which is predicted to lead to a truncated or absent protein. This is corroborated by a functional study that provides some evidence that this variant results in a truncated protein that lacks the BRCT domains (Caligo 2009 PMID:18680205). Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variant ID 17675). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PVS1_Strong.
Fulgent Genetics, Fulgent Genetics	RCV000763000	SCV000611253	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2021-10-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048523	SCV000699132	pathogenic	Hereditary breast ovarian cancer syndrome	2016-08-15	criteria provided, single submitter	clinical testing	Variant summary: The c.4327C>T (p.Arg1443X) variant in BRCA1 gene is a nonsense mutation. The mutation is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.000016 (2/121390 chrs tested). This frequency does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA1 (0.001). The variant has been reported in multiple HBOC families and was shown to segregate with disease phenotype. It has been classified as pathogenic by multiple reputable databases/clinical laboratories. Taken together, the variant was classified as Pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000019244	SCV000743394	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-10-08	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000019244	SCV000744615	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000235131	SCV000778740	pathogenic	not provided	2023-12-05	criteria provided, single submitter	clinical testing	PP5, PM2_moderate, PS4_moderate, PVS1
Fulgent Genetics, Fulgent Genetics	RCV000763000	SCV000893445	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2018-10-31	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000019244	SCV001434962	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2018-10-12	criteria provided, single submitter	clinical testing	This rare nonsense variant c.4327C>T (p.Arg1443*) in the BRCA1 gene is extremely rare in public databases and is predicted to introduce a premature translation termination codon. This variant is considered to be a founder mutation (PMID 15883839 ) and has been observed in multiple unrelated individuals with breast cancer (PMID 10422801,21324516, 7894491). Therefore, this c.4327C>T (p.Arg1443*) variant in the BRCA1 gene is classified as pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000235131	SCV001450289	pathogenic	not provided	2015-08-19	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000235131	SCV001762197	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000019244	SCV001934263	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-10-23	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000048523	SCV002025939	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131880	SCV002538287	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-09	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000235131	SCV002550977	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000235131	SCV003809801	pathogenic	not provided	2023-11-03	criteria provided, single submitter	clinical testing
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV000235131	SCV004042699	pathogenic	not provided	2023-10-17	criteria provided, single submitter	clinical testing	This variant has been identified by standard clinical testing. female patient with breast cancer Selected ACMG criteria: Not enough evidence
Baylor Genetics	RCV000019244	SCV004215050	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-02-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004802942	SCV004817682	pathogenic	BRCA1-related cancer predisposition	2024-09-23	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 12 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 30 individuals affected with breast, ovarian and uterine cancer (PMID: 7894491, 10422801, 10682662, 11179017, 15726418, 17221156, 19656415, 19863560, 20104584, 21324516, 22798144, 26681312, 27553291, 28724667, 28993434, 29470806, 33471991; Leiden Open Variation Database DB-ID BRCA1_000312). A breast cancer case-control meta-analysis detected this variant in 9/41890 cases and 1/41607 unaffected individuals with an OR 8.3 (95% CI 1.05-16.0) (PMID: 28283652). This variant has been detected in over 100 suspected hereditary breast and ovarian cancer families (PMID: 7493024, 16030099, 18821011, 19241424, 19329713, 21203900, 23233716, 29907814), in which haplotype analyses suggest that this was a founder mutation in the French-Canadian population and also arose independently worldwide (PMID: 9792861, 15883839, 23199084). This variant has been identified in 7/282760 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000019244	SCV005045970	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM5_PTC_Strong
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000235131	SCV005199717	pathogenic	not provided	2022-11-25	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000019244	SCV005329617	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-20	criteria provided, single submitter	clinical testing	The stop gained c.4327C>T (p.Arg1443Ter) variant in the BRCA1 gene as been observed in individual(s) with hereditary breast and ovarian cancer (Kim, Haeyoung et al., 2012). It is commonly reported in individuals of French Canadian ancestry (Cavallone, Luca et al., 2010). This variant is reported with the allele frequency (0.002%) in the gnomAD Exomes. It is submitted to ClinVar as Pathogenic (reviewed by expert panel). This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. The nucleotide change c.4327C>T in BRCA1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000019244	SCV000039532	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1994-12-01	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000019244	SCV000109372	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2013-11-14	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000019244	SCV000145057	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Bioinformatics dept., Datar Cancer Genetics Limited, India	RCV000159989	SCV000280026	pathogenic	Familial cancer of breast		no assertion criteria provided	case-control
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000048523	SCV000587391	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353404	SCV000591505	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Arg1443X variant has been previously and extensively reported in the literature. In two selected publications, this variant was identified in 18 of 294 individuals with hereditary breast and ovarian cancer (Selected publications: Tonin 1998, Castilla 1994). This variant was identified as a founder French-Canadian mutation and a common haplotype was described; multiple individuals from these families had breast or ovarian cancers; additional data suggest this variant may also have arisen independently at least three times. The variant is described 83 times in the UMD database as "causal" and 126 times in the BIC database as clinically important. The p.Arg1443X variant leads to a premature stop codon at position 1443, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000019244	SCV000733611	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735445	SCV000863581	pathogenic	Breast and/or ovarian cancer	2015-12-07	no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000048523	SCV001749723	not provided	Hereditary breast ovarian cancer syndrome		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 04-30-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000235131	SCV001905764	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000235131	SCV001958778	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000019244	SCV002588810	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing